Browsing by Author "Gallant, Maxime A."
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Item Bisphosphonate Binding Affinity Affects Drug Distribution in Both Intracortical and Trabecular Bone of Rabbits(Springer, 2012) Turek, John; Ebetino, F. Hal; Lundy, Mark W.; Sun, Shuting; Kashemirov, Boris A.; McKenna, Charles E.; Gallant, Maxime A.; Plotkin, Lilian I.; Bellido, Teresita; Duan, Xuchen; Triffitt, James T.; Russell, R. Graham G.; Burr, David B.; Allen, Matthew R.; Anatomy, Cell Biology and Physiology, School of MedicineDifferences in the binding affinities of bisphosphonates for bone mineral have been proposed to determine their localizations and duration of action within bone. The main objective of this study was to test the hypothesis that mineral binding affinity affects bisphosphonate distribution at the basic multicellular unit (BMU) level within both cortical and cancellous bone. To accomplish this objective, skeletally mature female rabbits (n = 8) were injected simultaneously with both low- and high-affinity bisphosphonate analogs bound to different fluorophores. Skeletal distribution was assessed in the rib, tibia, and vertebra using confocal microscopy. The staining intensity ratio between osteocytes contained within the cement line of newly formed rib osteons or within the reversal line of hemiosteons in vertebral trabeculae compared to osteocytes outside the cement/reversal line was greater for the high-affinity compared to the low-affinity compound. This indicates that the low-affinity compound distributes more equally across the cement/reversal line compared to a high-affinity compound, which concentrates mostly near surfaces. These data, from an animal model that undergoes intracortical remodeling similar to humans, demonstrate that the affinity of bisphosphonates for the bone determines the reach of the drugs in both cortical and cancellous bone.Item Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties(2014) Gallant, Maxime A.; Brown, Drew M.; Hammond, Max; Wallace, Joseph M.; Du, Jiang; Deymier-Black, Alix C.; Almer, Jonathan D.; Stock, Stuart R.; Allen, Matthew R.; Burr, David B.Raloxifene is an FDA approved agent used to treat bone loss and decrease fracture risk. In clinical trials and animal studies, raloxifene reduces fracture risk and improves bone mechanical properties, but the mechanisms of action remain unclear because these benefits occur largely independent of changes to bone mass. Using a novel experimental approach, machined bone beams, both from mature male canine and human male donors, were depleted of living cells and then exposed to raloxifene ex vivo. Our data show that ex vivo exposure of non-viable bone to raloxifene improves intrinsic toughness, both in canine and human cortical bone beams tested by 4-point bending. These effects are cell-independent and appear to be mediated by an increase in matrix bound water, assessed using basic gravimetric weighing and sophisticated ultrashort echo time magnetic resonance imaging. The hydroxyl groups (-OH) on raloxifene were shown to be important in both the water and toughness increases. Wide and small angle x-ray scattering patterns during 4-pt bending show that raloxifene alters the transfer of load between the collagen matrix and the mineral crystals, placing lower strains on the mineral, and allowing greater overall deformation prior to failure. Collectively, these findings provide a possible mechanistic explanation for the therapeutic effect of raloxifene and more importantly identify a cell-independent mechanism that can be utilized for novel pharmacological approaches for enhancing bone strength.Item Effects of Dietary Protein Source and Quantity on Bone Morphology and Body Composition Following a High-Protein Weight-Loss Diet in a Rat Model for Postmenopausal Obesity(MDPI, 2022-05-28) Wright, Christian S.; Hill, Erica R.; Reyes Fernandez, Perla C.; Thompson, William R.; Gallant, Maxime A.; Campbell, Wayne W.; Main, Russell P.; Physical Therapy, School of Health and Human SciencesHigher protein (>30% of total energy, HP)-energy restriction (HP-ER) diets are an effective means to improve body composition and metabolic health. However, weight loss (WL) is associated with bone loss, and the impact of HP-ER diets on bone is mixed and controversial. Recent evidence suggests conflicting outcomes may stem from differences in age, hormonal status, and the predominant source of dietary protein consumed. Therefore, this study investigated the effect of four 12-week energy restriction (ER) diets varying in predominate protein source (beef, milk, soy, casein) and protein quantity (normal protein, NP 15% vs. high, 35%) on bone and body composition outcomes in 32-week-old obese, ovariectomized female rats. Overall, ER decreased body weight, bone quantity (aBMD, aBMC), bone microarchitecture, and body composition parameters. WL was greater with the NP vs. HP-beef and HP-soy diets, and muscle area decreased only with the NP diet. The HP-beef diet exacerbated WL-induced bone loss (increased trabecular separation and endocortical bone formation rates, lower bone retention and trabecular BMC, and more rod-like trabeculae) compared to the HP-soy diet. The HP-milk diet did not augment WL-induced bone loss. Results suggest that specific protein source recommendations may be needed to attenuate the adverse alterations in bone quality following an HP-ER diet in a model of postmenopausal obesity.Item Elevated Mechanical Loading When Young Provides Lifelong Benefits to Cortical Bone Properties in Female Rats Independent of a Surgically Induced Menopause(2013-09) Warden, Stuart J.; Galley, Matthew R.; Hurd, Andrea L.; Wallace, Joseph M.; Gallant, Maxime A.; Richard, Jeffrey S.; George, Lydia A.Exercise that mechanically loads the skeleton is advocated when young to enhance lifelong bone health. Whether the skeletal benefits of elevated loading when young persist into adulthood and after menopause are important questions. This study investigated the influence of a surgically induced menopause in female Sprague-Dawley rats on the lifelong maintenance of the cortical bone benefits of skeletal loading when young. Animals had their right forearm extrinsically loaded 3 d/wk between 4 and 10 weeks of age using the forearm axial compression loading model. Left forearms were internal controls and not loaded. Animals were subsequently detrained (restricted to cage activities) for 94 weeks (until age 2 years), with ovariectomy (OVX) or sham-OVX surgery being performed at 24 weeks of age. Loading enhanced midshaft ulna cortical bone mass, structure, and estimated strength. These benefits persisted lifelong and contributed to loaded ulnas having greater strength after detraining. Loading also had effects on cortical bone quality. The benefits of loading when young were not influenced by a surgically induced menopause because there were no interactions between loading and surgery. However, OVX had independent effects on cortical bone mass, structure, and estimated strength at early postsurgery time points (up to age 58 weeks) and bone quality measures. These data indicate skeletal loading when young had lifelong benefits on cortical bone properties that persisted independent of a surgically induced menopause. This suggests that skeletal loading associated with exercise when young may provide lifelong antifracture benefits by priming the skeleton to offset the cortical bone changes associated with aging and menopause.Item In vivo reference point indentation reveals positive effects of raloxifene on mechanical properties following six months of treatment in skeletally mature beagle dogs.(Published article can be found at: http://www.sciencedirect.com/science/article/pii/S8756328213002718 doi: 10.1016/j.bone.2013.07.009, 2013) Aref, Mohammad; Gallant, Maxime A.; Organ, Jason M.; Wallace, Joseph M.; Newman, Christopher L.; Burr, David B.; Brown, Drew M.; Allen, Matthew R.Raloxifene treatment has been shown previously to positively affect bone mechanical properties following one year of treatment in skeletally mature dogs. Reference point indentation (RPI) can be used for in vivo assessment of mechanical properties and has been shown to produce values that are highly correlated with properties derived from traditional mechanical testing. The goal of this study was to use RPI to determine if raloxifene-induced alterations in mechanical properties occurred after 6 months of treatment. Twelve skeletally mature female beagle dogs were treated for 6 months with oral doses of saline vehicle (VEH, 1 ml/kg/day) or a clinically relevant dose of raloxifene (RAL, 0.5 mg/kg/day). At six months, all animals underwent in vivo RPI (10 N force, 10 cycles) of the anterior tibial midshaft. RPI data were analyzed using a custom MATLAB program, designed to provide cycle-by-cycle data from the RPI test and validated against the manufacturer-provided software. Indentation distance increase (IDI), a parameter that is inversely related to bone toughness, was significantly lower in RAL-treated animals compared to VEH (-16.5%) suggesting increased bone toughness. Energy absorption within the first cycle was significantly lower with RAL compared to VEH (-21%). These data build on previous work that has documented positive effects of raloxifene on material properties by showing that these changes exist after 6 months.Item Multiscale analysis of morphology and mechanics in tail tendon from the ZDSD rat model of type 2 diabetes(2014-02) Gonzalez, Armando Diaz; Gallant, Maxime A.; Burr, David B.; Wallace, Joseph M.Type 2 diabetes (T2D) impacts multiple organ systems including the circulatory, renal, nervous and musculoskeletal systems. In collagen-based tissues, one mechanism that may be responsible for detrimental mechanical impacts of T2D is the formation of advanced glycation end products (AGEs) leading to increased collagen stiffness and decreased toughness, resulting in brittle tissue behavior. The purpose of this study was to investigate tendon mechanical properties from normal and diabetic rats at two distinct length scales, testing the hypothesis that increased stiffness and strength and decreased toughness at the fiber level would be associated with alterations in nanoscale morphology and mechanics. Individual fascicles from female Zucker diabetic Sprague-Dawley (ZDSD) rats had no differences in fascicle-level mechanical properties but had increased material-level strength and stiffness versus control rats (CD). At the nanoscale, collagen fibril D-spacing was shifted towards higher spacing values in diabetic ZDSD fibrils. The distribution of nanoscale modulus values was also shifted to higher values. Material-level strength and stiffness from whole fiber tests were increased in ZDSD tails. Correlations between nanoscale and microscale properties indicate a direct positive relationship between the two length scales, most notably in the relationship between nanoscale and microscale modulus. These findings indicate that diabetes-induced changes in material strength and modulus were driven by alterations at the nanoscale.Item Multiscale analysis of morphology and mechanics in tail tendon from the ZDSD rat model of type 2 diabetes(Elsevier, 2014-02-07) Gonzalez, Armando Diaz; Gallant, Maxime A.; Burr, David B.; Wallace, Joseph M.; Department of Orthopaedic Surgery, IU School of MedicineType 2 diabetes (T2D) impacts multiple organ systems including the circulatory, renal, nervous and musculoskeletal systems. In collagen-based tissues, one mechanism that may be responsible for detrimental mechanical impacts of T2D is the formation of advanced glycation end products (AGEs) leading to increased collagen stiffness and decreased toughness, resulting in brittle tissue behavior. The purpose of this study was to investigate tendon mechanical properties from normal and diabetic rats at two distinct length scales, testing the hypothesis that increased stiffness and strength and decreased toughness at the fiber level would be associated with alterations in nanoscale morphology and mechanics. Individual fascicles from female Zucker diabetic Sprague-Dawley (ZDSD) rats had no differences in fascicle-level mechanical properties but had increased material-level strength and stiffness versus control rats (CD). At the nanoscale, collagen fibril D-spacing was shifted towards higher spacing values in diabetic ZDSD fibrils. The distribution of nanoscale modulus values was also shifted to higher values. Material-level strength and stiffness from whole fiber tests were increased in ZDSD tails. Correlations between nanoscale and microscale properties indicate a direct positive relationship between the two length scales, most notably in the relationship between nanoscale and microscale modulus. These findings indicate that diabetes-induced changes in material strength and modulus were driven by alterations at the nanoscale.Item Nanoscale Changes in Collagen are Reflected in Physical and Mechanical Properties of Bone at the Microscale in Diabetic Rats(2014-03) Hammond, Max A.; Gallant, Maxime A.; Burr, David B.; Wallace, Joseph M.Diabetes detrimentally affects the musculoskeletal system by stiffening the collagen matrix due to increased advanced glycation end products (AGEs). In this study, tibiae and tendon from Zucker diabetic Sprague–Dawley (ZDSD) rats were compared to Sprague–Dawley derived controls (CD) using Atomic Force Microscopy. ZDSD and CD tibiae were compared using Raman Spectroscopy and Reference Point Indentation (RPI). ZDSD bone had a significantly different distribution of collagen D-spacing than CD (p = 0.015; ZDSD n = 294 fibrils; CD n = 274 fibrils) which was more variable and shifted to higher values. This shift between ZDSD and CD D-spacing distribution was more pronounced in tendon (p < 0.001; ZDSD n = 350; CD n = 371). Raman revealed significant increases in measures of bone matrix mineralization in ZDSD (PO43 − ν1/Amide I p = 0.008; PO43 − ν1/CH2 wag p = 0.047; n = 5 per group) despite lower bone mineral density (aBMD) and ash fraction indicating diabetes may preferentially reduce the Raman signature of collagen. Decreased indentation distance increase (p = 0.010) and creep indentation distance (p = 0.040) measured by RPI (n = 9 per group) in ZDSD rats suggest a matrix more resistant to indentation under the high stresses associated with RPI at this length scale. There were significant correlations between Raman and RPI measurements in the ZDSD population (n = 18 locations) but not the CD population (n = 16 locations) indicating that while RPI is relatively unaffected by biological noise, it is sensitive to disease-induced compositional changes. In conclusion, diabetes in the ZDSD rat causes changes to the nanoscale morphology of collagen that result in compositional and mechanical effects in bone at the microscale.Item A novel approach to evaluate the effect of medicaments used in endodontic regeneration on root canal surface indentation(The final publication is available at: http://link.springer.com/article/10.1007%2Fs00784-013-1125-x doi: 10.1007/s00784-013-1125-x, 2013-10) Yassen, Ghaeth H.; Chu, Tien-Min G.; Gallant, Maxime A.; Allen, Matthew R.; Vail, Mychel M.; Murray, Peter E.; Platt, Jeffrey A.Objectives: To investigate the capability of a novel reference point indentation apparatus to test the indentation properties of root canal surface dentine treated with three intracanal medicaments used in endodontic regeneration. Materials and Methods: Immature human premolars were selected (n=22). Four specimens were obtained from each root and randomly assigned to three treatment groups and a control group. Each specimen was exposed to one of three treatment pastes (triple antibiotic (TAP), double antibiotic (DAP), or calcium hydroxide [Ca(OH)2] or neutral de-ionized water (control) for one or four weeks. After each time-interval, the indentation properties of the root canal dentine surfaces were measured using a BioDent reference point indenter. Two-way ANOVA and Fisher’s Protected Least Significant Differences were used for statistical analyses. Results: Significant differences in indentation parameters and estimated hardness between all groups at both time points were found. TAP treated dentine had the highest significant indentation parameters, followed by DAP treated dentine, untreated control dentine and Ca(OH)2 treated dentine, respectively. Furthermore, TAP treated dentine had the lowest significant estimated hardness, followed by DAP treated dentine, untreated control dentine and Ca(OH)2 treated dentine, respectively. Conclusion: BioDent reference point indenter was able to detect significant differences in indentation properties of root canal dentine treated with various medicaments. Clinical Relevance: The use of a reference point indenter is a promising approach to characterize the indentation properties of root canal surfaces without any surface modification. This might provide an in vitro mechanical measurement that is more representative of the actual clinical situation.Item Raloxifene Prevents Skeletal Fragility in Adult Female Zucker Diabetic Sprague-Dawley Rats(2014-09-22) Hill Gallant, Kathleen M.; Gallant, Maxime A.; Brown, Drew M.; Sato, Amy Y.; Wiliams, Justin N.; Burr, David B.